Project Abstract Osteoporosis is a well known consequence of sex-hormone deficiency, but bone loss starts in the 30s and continues steadily after gonadal failure. There are thus several causes for the bone loss associated with aging. In this application, we ask whether osteoporosis might have a neuroskeletal component. The proposal stems from an increasing amount of preclinical data suggesting that sympathetic nerves, which richly innervate the skeleton, control the process of bone remodeling. We and others have shown that activation of sympathetic nerves in mice causes the release of norepinephrine (NE) and the stimulation of the ?2-adrenergic receptors (?2AR) in osteoblasts, leading to a Rankl-dependent increase in bone resorption and to a Clock-dependent reduction in bone formation, hence to bone loss. However, the clinical relevance of these findings remains unclear. Three critical observations are at the core of this proposal: 1) parasympathetic and sympathetic outflow changes in an inverse manner with age and these changes correlate with bone accrual and bone loss, respectively; 2) bone loss occurs prematurely in patients with Alzheimer disease (AD), at early stage of the disease, prior to reduced locomotor activity and skeletal unloading typical of late-stage AD, and this is also associated with low parasympathetic and high sympathetic tone; 3) our data support the existence of an endogenous homeostatic system, driven by the norepinephrine transporter (NET) in osteocytes, controlling the skeleton?s response to overt activity of sympathetic nerves, which become dysfunctional upon aging. Based on these observations, the main hypothesis of this proposal is that a shift from a dominant parasympathetic tone in young individuals to a dominant sympathetic tone in older individuals contributes to age-related bone loss. We have designed experiments to determine if a high central parasympathetic tone is beneficial for bone density accrual, and if a premature or overt reduction in parasympathetic tone during aging leads to bone loss (Aim 1). In Aim 2, we will determine if a reduction in NE uptake activity in osteocytes with age reduces the capacity of the skeleton to handle NE released from sympathetic nerves and contributes to age-related osteoporosis. Genetic and pharmacological approaches will be used in both aims to alter crucial components of the autonomic nervous system, in presynaptic neurons versus post-synaptic bone cells, and in young versus aging mice. This work will for the first time put previous findings related to the autonomic nervous system and bone into the clinically relevant context of aging. It could impact the management of osteoporosis by supporting the use of approaches that counteract not only the negative effect of sex hormone deficiency on bone but also the early, progressive and sustained effects of the autonomic nervous system on bone homeostasis.